The overall objective of this proposal is to accelerate the acquisition of structural information about membrane proteins by applying a structural genomics approach informed by experience gained in studies driven by biological and biochemical problems. We propose to establish the New York Consortium on Membrane Protein Structure (NYCOMPS) to work collectively toward this objective. A pipeline for structure determination will be established starting from a bioinformatics analysis of all known sequences, moving on to recombinant cloning, protein expression and protein purification at moderate throughput, and then into structure determination by x-ray crystallography and NMR spectroscopy. A Protein Production Facility will be established in laboratories of the New York Structural Biology Center (NYSBC), and other activities will be carried out in the laboratories of NYCOMPS participants. We build on experience gained in addressing the structural biology of membrane protein structure in our own laboratories and from our participation in two pilot projects of the Protein Structure Initiative, the Northeast Structural Genomics Consortium (NESG) and the New York Structural Genomics Research Consortium (NYSGXRC). We also propose to conduct research aimed at improving the process, carried out both in the Protein Production Facility and also in several of the laboratories of participants. Milestones have been set for an initial exponential increase in structural output followed by linear growth later in the course of this five-year project. We expect that structural results from this initiative will provide greater biological insight for proteins having a putative function, afford an opportunity for biological discovery for those of unknown function, and give a deeper understanding of biophysical principles that underlie membrane protein structure generally. Methods derived in this work will also return benefits to our individual studies on well characterized biological problems.